PROJECT SUMMARY A possible link between posttraumatic stress disorder (PTSD) and ischemic heart disease (IHD) has been suggested, but evidence for a causal connection is limited due to shortage of prospective studies using objective measures of IHD. In addition, potential mechanisms remain unclear. A biological hallmark of PTSD is enhanced sympathetic nervous system (SNS) activity with stress, especially in response to trauma-reminiscent stimuli. Our overarching hypothesis is that repeated SNS activation with trauma reminders in PTSD leads to microvascular dysfunction, endothelial injury and immune activation which, in turn, increase the risk of myocardial ischemia and acute coronary syndromes. The proposed project is a follow-up study of 281 male twin pairs (562 individuals) from the Vietnam Era Twin Registry 10 years after their baseline visit when they were extensively phenotyped, including assessment of IHD with positron emission tomography (PET) myocardial perfusion imaging. In about 180 pairs, we will repeat PET imaging to obtain longitudinal quantitative indicators of IHD. Furthermore, we will administer standardized traumatic memory tasks to examine vascular and immune responses to stress. In addition to a longitudinal design, state-of-the art measures of IHD, and consideration of novel mechanisms, this project has the advantage of a twin sample, which will allow us to control for genetic and familial influences and parse the relative contributions of genes and shared/unshared environment to the association between PTSD and IHD. The aims are: (1) Examine if PTSD is related to worsening of IHD measured longitudinally with PET myocardial perfusion imaging (summed total severity score of myocardial perfusion, and coronary flow reserve); (2) Examine if PTSD is related to adverse vascular and immune responses during traumatic memory tasks (peripheral vasoconstriction by means of pulsatile arterial tonometry, and markers of endothelial injury and inflammation: circulating progenitor cells and adhesion molecules). For both aims, we will assess if effects are independent of genetics, shared environment and traditional cardiovascular risk factors. In addition, we will investigate vulnerability and resilience factors, including type of trauma (e.g., combat vs. noncombat), childhood trauma, depression comorbidity, social support, and PTSD trajectory (duration of PTSD, PTSD remission), and whether vascular and immune responses to trauma reminders predict IHD. Our rigorous twin study will sharpen the understanding of the links between PTSD and IHD, and test the new paradigm that immune and vascular reactivity during trauma reminders play a fundamental role. This research should fill a significant gap in evidence regarding the long-term cardiovascular consequences of PTSD, and potentially help in the development of new methods for risk prediction and prevention to reduce the burden of IHD among persons with PTSD. These data should facilitate incorporating stress processes into the mainstream of cardiovascular research and clinical practice, which is exceedingly overdue.